The invention relates to devices and methods for the management of pain. Particularly, the invention relates to an implanted drug delivery device used to deliver a potent pain-killing drug over a protracted period of time.
Many medications are used for the treatment of pain, ranging from well known, over-the-counter compounds such as aspirin, acetaminophen, ibuprofen and other non-steroidal anti-inflammatory compounds to the newly developed chemical entities such as the cyclooxygenase II inhibitor compounds. Opiates in various forms, including opium, heroine and morphine which derive from the opium poppy, have very powerful analgesic properties. Opiates have been widely used for anesthesia as well for the treatment of pain, especially where the pain is very severe. In addition to these natural opiates, many synthetic opioids have since been synthesized including methadone, fentanyl and congeners of fentanyl such as sufentanil, alfentanil, lofentanil, carfentanil, remifentanil, etc. Of the opioids, morphine is still the drug of choice for management of pain at least in part due to its low cost, the ability of the drug to provide relief from pain of a variety of origins, and the vast experience with this drug. Despite its therapeutic advantages and vast experience with the drug, many pain management experts believe that morphine and other opioids are under-prescribed for patients who require long-term pain therapy.
One reason for underprescription is the risk of the side effects associated with long-term administration of opioids in general, such as development of opiate tolerance, dependence, constipation, and/or other undesirable side effects (see, e.g., Moulin et al. 1992 Can Med. Assoc. J. 146:891-7). Patients who develop opioid tolerance require increased doses to achieve a satisfactory analgesic effect, and risk the development of further undesirable side effects such as respiratory depression, which can be life threatening. Physical dependence, which is related to factors such as the dose administered and the length of the administration period, can generally only be resolved by discontinuing opioid administration, which in turn results in the onset of severely painful withdrawal symptoms. Other side effects that can be associated with administration of opioids include reduced cough reflex, bronchial spasms, nausea, vomiting, peripheral vasodilation, orthostatic hypotension, vagal impact on the heart, contraction of smooth muscles (sphincters), reduced peristaltic motility in the gastrointestinal tract (e.g., constipation), urinary retention, changes in regulation of body temperature and sleep pattern, and release of histamine, adrenalin, and anti-diuretic hormone. The negative effects on respiratory function especially impact postoperative patients, who are particularly susceptible to depression of respiratory function. Even where the concerns regarding side effects might be outweighed by the serious need for pain relief as in terminally ill patients, many doctors still avoid prescribing opioids due to concerns of abuse of surplus medication by others in contact with the patient, or even that their frequent prescription of the drug might lead to criminal investigation.
In addition to the disadvantages listed above pertaining to opioids in general, morphine itself has also been associated with particular side effects, at times so severe as to make such therapy intolerable, especially for patients who are on long-term pain therapy or who require high doses of medication to obtain relief. Some of these side effects associated with morphine usage, particularly at high doses, include nausea and vomiting (see for example Paix et al. (1995) Pain 63:263-9) and severe constipation. In addition, Sjorgen et al. (1994 Pain 59:313-316) have reported the phenomena of hyperalgesia (increased response to certain stimulus which is not normally painful), allodynia (sensation of pain felt even when stimulus is not normally painful) and myoclonus associated with morphine use. It has been hypothesized that morphine and its metabolites may induce such abnormal sensitivity (see, e.g., Sjorgen et al. (1994) Pain 59:313-316).
Fentanyl and its congeners were originally developed as anesthesia agents, and are generally used in the United States for the limited purposes of intravenous administration in balanced general anesthesia, as a primary anesthetic, or, in the case of sufentanil, for epidural administration during labor and delivery. However, these drugs also have powerful analgesic properties and are several hundred or thousand times more potent than morphine depending on the particular congener. A few studies have in fact suggested that fentanyl and its congeners be used instead of morphine due to their increased potency and decreased side effects relative to morphine (see e.g., Sjorgen et al. (1994) Pain 59:313-316 and Paix et al. (1995) Pain 63:263-9). Fentanyl and its congeners are, however, more difficult to administer than morphine since they are not orally absorbed, are extremely potent (requiring very precise, accurate dosing of small amounts) and have very short half lives in the body thus requiring frequent dosing. For these reasons, conventional methods for delivery of opioid analgesics are inadequate to meet these delivery requirements. For example, fentanyl has been administered in single, small intravenous doses, but this method of administration, besides being impractical for long-term therapy, results in a short duration of action and rapid recovery due to a redistribution into fat stores and a rapid decline in plasma concentration. The development of transdermal patch delivery technology allowed fentanyl to be delivered continuously through the skin (e.g., the commercial Duragesic(trademark) transdermal patch). Since the transdermal delivery method provided for constant drug delivery, it was a marked improvement relative to bolus injection; however, transdermal delivery also has several limitations. For example, transdermal delivery is disadvantageous in that the dose of drug that can be delivered is limited by the available skin surface area, thus making transdermal delivery suitable for low-to-medium opioid dose requirements, but often inadequate for more high dose requirements. In addition, transdermal delivery of drug is disadvantageous in that there is a delay in obtaining steady state plasma concentrations upon initiation of therapy, as well as a prolonged period of continued effect even after removal of the patch. Other problems associated with transdermal delivery include skin irritation, loss of adhesion after exposure to moisture (e.g., perspiration, bathing) the potential for diversion of drug for illicit purposes and patient distaste for the unsightliness of highly visible patches.
While subcutaneous infusion of fentanyl and sufentanil have been the subject of experimentation on a limited basis, the methods disclosed in the prior art are impractical as long-term pain therapies. Paix et al. (1995 Pain 63:263-9), for example, discloses the use of subcutaneous fentanyl and sufentanil as an alternative therapy in a small number of patients who suffered significant side effects associated with administration of morphine. In Paix et al., the drug was infused into the subcutaneous space in relatively low drug concentrations and at relatively large volume rates (e.g., on the order of 3 mL/day to 40 mL/day) via an external syringe driver. The treatment method disclosed by Paix et al. has several major disadvantages that render it impractical for long-term therapy. First, the provision of drug from an external source adversely affects mobility of the patient and is therefore inconvenient for ambulatory patients, increases the risk of infections at the subcutaneous delivery site and provides an opportunity for drug to be diverted for illicit uses. Second, the infusion of large volumes of fluid may result in tissue damage or edema at the site of infusion. In addition, the absorptive capacity of the subcutaneous space limits the volume of fluid that can be delivered (see, e.g., Anderson et al., supra), and this volumetric limitation can in turn limit the amount of drug that can be administered (e.g., in Paix et al., more potent opioids were administered to some patients requiring high doses since the volume of morphine required was too large to be effectively absorbed in the subcutaneous tissues).
As is evident from the above, there is a great need for devices and methods for effective and practical management of pain, particularly pain of long duration, with better efficacy and reduced side effects. The present invention addresses this problem.
The invention features devices and methods for treatment of pain. The drug delivery device is a controlled drug delivery system adapted for whole implantation in a subject and to provide pain relief by delivery of fentanyl or a fentanyl congener (e.g., sufentanil) over a protracted period of time (e.g., at least about 3 days or more than about 3 days). The device comprises a housing defining a reservoir that contains a drug formulation, a pump operatively connected to the housing so as to facilitate movement of drug out of the reservoir and out of the device, and a thermal expansion element which defines a flow pathway comprising a thermal expansion channel to accommodate thermal expansion of formulation in the reservoir. The device can further comprise a valve positioned within the flow pathway so as to prevent movement of drug out of the reservoir prior to use.
Accordingly, in one aspect the invention features a controlled drug delivery device, adapted for whole implantation, the device comprising a housing defining a reservoir, the reservoir containing a formulation comprising a drug selected from the group consisting of fentanyl or a fentanyl congener, wherein the drug is present in an amount sufficient for treatment of pain in a subject for a period of at least about 3 days; a pump operatively connected to the housing; and a thermal expansion element comprising an inlet, a thermal expansion channel adapted to contain a volume of formulation associated with thermal expansion. In use, the inlet, thermal expansion channel, and outlet define a flow pathway from the reservoir and out of the device such that actuation of the pump effects movement of formulation through the flow pathway.
In specific embodiments, the thermal expansion element comprises a flow pathway that is at least partially defined by a plug, which plug can be seated within the housing. In other embodiments the thermal expansion element comprises a flow pathway is at least partially defined by a plug seated within the device housing, and by the plug and an inner wall of the housing.
In further specific embodiments, the thermal expansion element comprises a valve positioned and adapted for maintaining a sealed reservoir until opened. In related embodiments, the thermal expansion element comprises a plunger, the plunger having at least a portion slidably positioned within the flow pathway and having a portion seated within the valve such that when in a closed position the plunger and valve occlude the flow pathway to prevent movement of formulation out of the outlet.
In further specific embodiments, the flow pathway narrows from a wider inlet and thermal expansion channel to a narrower outlet.
In still further embodiments, the device is adapted for delivery of drug at a rate of from about 0.01 micrograms per hour to 2000 micrograms per hour.
In another embodiment, the drug in the formulation in the reservoir is present in a concentration of about 5 mg/mL to about 400 mg/mL.
In an embodiment of particular interest, the drug is sufentanil.
In another aspect, the invention features a method of treating pain in a subject, the method comprising wholly implanting at an implantation site in a subject a drug delivery device as described above, and parenterally delivering the formulation from the drug delivery device to the subject so that drug enters the systemic circulation and is transported thereby to a site of action in an amount sufficient to treat pain.
In specific embodiments, the drug delivery device is implanted at a subcutaneous site from which drug delivered from the device is released into the subcutaneous site, and then into the systemic circulation. In further specific embodiments, the formulation is delivered at a volume rate of from about 0.01 xcexcl/day to 2 ml/day. In still other embodiments, the drug is delivered at a rate of from about 0.01 xcexcg per hour to 2,000 xcexcg per hour. In further embodiments, drug is delivered for a period of from about 4 weeks to 12 months. In another embodiment, the device comprises an amount of drug sufficient to provide for alleviation of pain in a subject for a period of more than 30 days. In an embodiment of particular interest, the drug is sufentanil.
One advantage of the invention is that the devices and methods described herein provide effective management of pain by administration of a relatively small quantity of fentanyl or a fentanyl congener (e.g., sufentanil), providing adequate pain relief and an improvement in adverse side effects relative to opioids, such as morphine (e.g., decreased gastrointestinal cramping). Given the adverse effects of opioid analgesics, this advantage is of considerable benefit to those requiring pain relief, particularly in relatively long term (e.g., 1-4 months) pain situations. Furthermore, the method may be more cost-effective, and thus may make pain management available to a broader population.
Another advantage of the invention is that the invention can be used to deliver relatively small quantities of fentanyl and fentanyl congeners accurately and precisely and thus safely delivering such drugs despite the extreme potency of these drugs compared to morphine. Thus, the invention allows for the convenient use of these drugs for treatment of pain ranging in severity from mild to severe.
One particular advantage of the invention is that an amount of fentanyl or a fentanyl congener sufficient to provide a relatively long duration of therapy can be stored safely and stably within the body and without deleterious effect given the high potency of the subject compounds.
Another advantage is that the drug delivery devices stores the drug formulation safely during use (e.g., without dose dumping), and release the drug formulation in a controlled fashion at a therapeutically effective rate to treat pain. Thus the devices and methods of the invention obviate undesirable bolus delivery upon implantation.
An important advantage of the invention is that the thermal expansion element accommodates thermal expansion of the formulation in the reservoir, thus minimizing the risk of initial increase of drug release due to thermal expansion of the formulation upon implantation into the body.
Another notable advantage of the invention is that the use of an implantable drug delivery device avoids the need for placement of external needles and/or catheters in the subject, which cause discomfort and can provide sites susceptible to infection. In addition, use of an implanted device increases patient compliance with a prescribed therapeutic regimen, substantially decreases or completely avoids the risk of abuse of the drug by the patient or others in contact with the patient, and affords greater mobility and easier outpatient management.
Another advantage of the invention is that fentanyl or a fentanyl congener can be delivered into the systemic circulation with such accuracy and precision and at such low quantities as to permit long-term use of such compounds to treat pain.
A further advantage is that a therapeutically effective dose of fentanyl and fentanyl congeners can be delivered at such relatively low volume rates, e.g., from about 0.01 xcexcl/day to 2 ml/day so as to minimize tissue disturbance or trauma.
Another advantage of the invention is that substantially continuous delivery of small quantities of fentanyl or fentanyl congener (e.g., sufentanil) is effective in long-term (e.g., chronic) administration (e.g., from several weeks or from about 1 to 12 months or more).
The method of the invention is also advantageous in that since the selected drugs (e.g., sufentanil) are highly lipophilic relative to other opioids, thus facilitating delivery of the drug across the blood-brain barrier. For example, the octanol/water partition coefficient of sufentanil is 1,727, compared to a coefficient of 1.4 for morphine. Systemic administration (e.g., by subcutaneous delivery) of certain lipophilic fentanyl congeners, e.g., sufentanil, may be as effective as if the drug were delivered directly to the central nervous system.
Still another advantage is that the invention may decrease the severity or incidence of side effects normally associated with use of morphine in pain management.
Still another advantage is that the invention reduces the potential for diversion of the drug from the intended recipient, prevents the user from accidental or intentional unprescribed alteration of dose, and therefore reduces the potential for drug abuse.
These and other advantages of the invention will be readily apparent to the ordinarily skilled artisan upon reading the present specification.